Claire M.B. Holloway

Variation in the Use of Percutaneous Biopsy for Diagnosis of Breast Abnormalities in Ontario

Preoperative diagnosis of breast abnormalities is currently the standard of care. A population-based study to determine the use of percutaneous needle biopsy for breast diagnosis in Ontario was performed. A total of 17,068 women undergoing breast tissue sampling (percutaneous needle biopsy or surgical excision) for diagnosis between April 1, 2002, and December 31, 2002, and without a previous cancer diagnosis were identified. Univariate and multivariate analyses examined the association of age, residence in a particular local health integration network (LHIN), income quintile, urban or rural residence, primary care provider, any prior mammogram, and prior regular screening mammography, as well as whether the biopsy was initiated by a screening mammogram with different methods of tissue diagnosis. A total of 10,459 women (61%) underwent percutaneous biopsy for diagnosis. A total of 10,131 women underwent surgery, of whom 6637 received a benign diagnosis and 3494 had cancer, for a benign-to-malignant ratio of 1.9:1. Women with cancer were slightly more likely to undergo percutaneous biopsy than women without (64.7% vs. 60.3%). There was variation among LHINs in the use of percutaneous biopsy (range, 24%–72%). Women with the highest incomes, urban residence, a primary care provider, or history of any prior mammography were more likely to receive percutaneous biopsy. On multivariate analysis, age 50 to 69 years, LHIN, urban residence, primary care provider, and screen-initiated evaluation were associated with percutaneous biopsy. Variation in the use of percutaneous biopsy by factors unrelated to indications for biopsy indicate that strategies to identify and overcome barriers to its use are needed.

A kit to prepare 111In-DTPA-trastuzumab (Herceptin) Fab fragments injection under GMP conditions for imaging or radioimmunoguided surgery of HER2-positive breast cancer

INTRODUCTION The human epidermal growth factor receptor-2 (HER2) gene is amplified in 25% of invasive breast cancers, and receptor overexpression has been noted in up to 60% of early stages of the disease [ductal carcinoma in situ (DCIS)]. Preclinical studies have revealed high tumor/blood ratios (>27:1) for (111)In-labeled Fab fragments of the HER2 monoclonal antibody, trastuzumab (Herceptin) ((111)In-DTPA-trastuzumab Fab) at 72 h pi in athymic mice bearing subcutaneous human breast cancer xenografts. Our aim in this study was to formulate a kit for preparation of (111)In-DTPA-trastuzumab Fab injection under good manufacturing practice (GMP) conditions suitable for human administration in a Phase I clinical trial of imaging and radioimmunoguided surgery (RIGS) of HER2-positive breast cancer. METHODS Fab fragments were produced by digestion of trastuzumab IgG (Herceptin) with immobilized papain for 20 h at 37°C. Fab fragments were purified by ultrafiltration, then reacted with a 10-fold molar excess of diethylenetriaminepentaacetic acid (DTPA) dianhydride. DTPA-Fab fragments were purified, then sterilized by filtration into unit dose glass vials (kits). Kits were tested against specifications for volume (0.9-1.1 ml), protein concentration (0.45-0.55 mg/ml), pH (5.5-6.5), DTPA substitution (0.5-4.0 mol DTPA/mol Fab), appearance (clear, colorless and particle free), labeling efficiency (≥ 85%), and sterility and apyrogenicity (USP XXXII). Immunoreactivity of (111)In-DTPA-trastuzumab Fab towards HER2 was measured by saturation radioligand binding assays using SKBR-3 human breast cancer cells (specifications: K(a) = 0.6-9.6 × 10(7) L/mol; B(max) = 0.6-10.4 × 10(6) sites/cell). (111)In-DTPA-trastuzumab Fab injection was prepared by adding 80-100 MBq of (111)InCl(3) to a single kit vial and incubating for 30 min at room temperature. (111)In-DTPA-trastuzumab Fab was assayed for the amount of radioactivity and tested for pH, radiochemical purity (RCP), appearance and sterility. RESULTS Pure and homogeneous Fab fragments were produced. Eleven lots of kits met established quality specifications. The labeling efficiency with (111)In was 90.6 ± 2.2%. (111)In-DTPA-trastuzumab Fab bound specifically to HER2 on SKBR-3 cells (K(a) = 4.8 ± 2.5 × 10(7) L/mol and B(max) = 1.6 ± 0.8 × 10(6) sites/cell). Thirteen lots of (111)In-DTPA-trastuzumab injection met all established specifications. Kits were stable for 90 days and (111)In-DTPA-trastuzumab Fab injection was stable for 24 h stored at 4 °C. CONCLUSIONS A kit was formulated under GMP conditions for the preparation of (111)In-DTPA-trastuzumab Fab injection suitable for human administration. The kits were approved by Health Canada.

The Role of Cytokeratin 5/6 as an Adjunct Diagnostic Tool in Breast Core Needle Biopsies

In this article, the probability of finding malignancy on surgical excision after applying well-defined morphological criteria combined with immunohistochemical evaluation of cytokeratin 5/6 for the diagnosis of atypical ductal hyperplasia on core biopsies is examined. On the basis of morphology alone, the reviewers reclassified the diagnoses of 140 core biopsies as follows: atypical ductal hyperplasia (n = 64), ductal hyperplasia of usual type (n = 44), flat epithelial atypia (n = 11), and miscellaneous benign (n = 21). Cytokeratin 5/6 immunostain was negative in 85.7% of atypical ductal hyperplasia cases and positive in 77.8% of ductal hyperplasia of usual type cases. The probability of predicting malignancy in a surgical specimen following a core biopsy increased from 43.6% to 67.8% (P = .002) by adhering to defined criteria and using cytokeratin 5/6 immunostain. Expertise and adherence to defined criteria are required to establish an accurate diagnosis of atypical ductal hyperplasia. Cytokeratin 5/6 can be a useful adjunct in cases with ductal hyperplasia but not in columnar cell lesions, where it is universally negative.

Percutaneous Needle Biopsy for Breast Diagnosis: How Do Surgeons Decide?

BackgroundDespite the advent of guidelines recommending core needle biopsy (CNB) for diagnosis of breast abnormalities, it is underused in some jurisdictions. We sought to determine those factors influencing surgeons’ choices of breast biopsy techniques.MethodsWe surveyed 385 general surgeons in Ontario to first determine factors influencing the choice of fine-needle aspiration biopsy (FNAB), CNB, both or neither for diagnosis of breast abnormalities in six clinical scenarios with varying risk of malignancy. Second, respondents were asked to rate 15 patient, organizational, and system factors for their impact on choice of biopsy technique. Third, surgeons were asked to describe their three greatest barriers to provision of cancer care.ResultsResponse rate was 44%, and 126 provided answers to the survey questions. When there was a high risk of malignancy, CNB and/or FNAB were favored over surgical biopsy (83% to 97% compared with 41% for presumed benign lesions), and CNB was preferred for percutaneous biopsy over FNAB (58% to 79% compared with 1% to 18%). Patient and clinical factors (46% FNAB, 42% CNB), patient preference for biopsy technique (34%, 31%), and delayed access to CNB, rather than lack of equipment (11% FNAB, 8% CNB) or expertise for CNB or FNAB (15%, 12%), had the greatest reported impact on choice of biopsy technique.ConclusionsSurgeon preference for CNB is higher than actual use. Further research is needed to establish whether or how CNB use could be improved by support for shared decision making or facilitating access.

Clinical and prognostic factors associated with diagnostic wait times by breast cancer detection method

IntroductionAlthough prognostic differences between screen-detected, interval and symptomatic breast cancers are known, factors associated with wait times to diagnosis among these three groups have not been studied.MethodsOf the 16,373 invasive breast cancers diagnosed between January 1, 1995 and December 31, 2003 in a cohort of Ontario women aged 50 to 69, a random sample (N = 2,615) were selected for chart abstraction. Eligible women were classified according to detection method; screen-detected (n = 1181), interval (n = 319) or symptomatic (n = 406). Diagnostic wait time was calculated from the initial imaging or biopsy to breast cancer diagnosis. Logistic regression analysis examined associations between diagnostic wait times dichotomized as greater or less than the median and demographic, clinical and prognostic factors separately for each detection cohort.ResultsWomen who underwent an open biopsy had significantly longer than median wait times to diagnosis, compared to women who underwent a fine needle aspiration or core biopsy; (screen-detected OR = 2.76, 95% CI = 2.14-3.56; interval OR = 2.56, 95% CI = 1.50-4.35; symptomatic OR = 5.56, 95% CI = 3.33-9.30). Additionally, screen-detected breast cancers diagnosed with stage II and symptomatic cancers diagnosed at stage III or IV had significantly shorter diagnostic wait times compared to those diagnosed at stage 1 (OR = 0.66 95% CI = 0.50-0.87 and OR = 0.46, 95% CI = 0.25-0.85 respectively).ConclusionsOur study is consistent with expedited diagnostic work-up for breast cancers with more advanced prognostic features. Furthermore, women who had an open surgical biopsy had a greater than the median diagnostic wait time, irrespective of detection method.

Cost-effectiveness analysis of whole-mount pathology processing for patients with early breast cancer undergoing breast conservation.

BACKGROUND Obtaining accurate histopathologic detail for breast lumpectomy specimens is challenging because of sampling and loss of three-dimensional conformational features with conventional processing. The whole-mount (wm) technique is a novel method of serial pathologic sectioning designed to optimize cross-sectional visualization of resected specimens and determination of margin status. METHODS Using a Markov chain cohort simulation cost-effectiveness model, we compared conventional processing with wm technique for breast lumpectomies. Cost-effectiveness was evaluated from the perspective of the Canadian health care system and compared using incremental cost-effectiveness ratios (icers) for cost per quality-adjusted life-year (qaly) over a 10-year time horizon. Deterministic and probabilistic sensitivity analyses were performed to test the robustness of the model with willingness-to-pay (wtp) thresholds of

What is the burden of axillary disease after neoadjuvant therapy in women with locally advanced breast cancer

0-

Wait Times for Breast Cancer Surgery: Effect of Magnetic Resonance Imaging and Preoperative Investigations on the Diagnostic Pathway

100,000. Costs are reported in adjusted 2014 Canadian dollars, discounted at a rate of 3%. RESULTS Compared with conventional processing, wm processing is more costly (

Improving patient flow and timeliness in the diagnosis and management of breast abnormalities: the impact of a rapid diagnostic unit

19,989 vs.

Multidisciplinary assessment for immediate breast reconstruction: A new approach

18,427) but generates 0.03 more qalys over 10 years. The icer is